Submitted on January 30, 2007
Accepted on June 14, 2007
Preoptic nitric oxide attenuates endotoxic fever in guinea pigs by inhibiting the POA release of norepinephrine
Carlos Feleder1, Vit Perlik2, and Clark M. Blatteis3*
1 Basic and Pharmaceutical Sciences, Albany College of Pharmacy, Albany, New York, United States
2 Research, Zentiva a.s., Prague, xxx, Czech Republic
3 Dept. of Physiology & Biophysics, University of Tennessee, Memphis, Memphis, Tennessee, United States
* To whom correspondence should be addressed. E-mail: blatteis{at}physio1.utmem.edu.
Lipopolysaccharide (LPS) administration induces hypothalamic nitric oxide (NO); NO is antipyretic in the preoptic area (POA), but its mechanism of action is uncertain. LPS also stimulates the release of preoptic norepinephrine (NE), which mediates fever onset. Because NE upregulates NO synthases and NO induces cyclooxygenase (COX)-2-dependent prostaglandin (PG)E2, we investigated whether NO mediates the production of this central fever mediator. Conscious guinea pigs with intraPOA microdialysis probes received LPS iv (2 µg/kg) and, thereafter, an NO donor (SIN-1) or scavenger (carboxy-PTIO) intraPOA (20 µg/µl each, 2 µl/min, 6 h). Core temperature (Tc) was monitored constantly; dialysate NE and PGE2 were analyzed in 30-min collections. To verify the reported involvement of 
2-adrenoceptors (AR) in PGE2 production, clonidine (2-AR agonist, 2 µg/µ1) was microdialyzed with and without SIN-1 or carboxy-PTIO. To assess the possible involvement of oxidative NE and/or NO products in the demonstrated initially COX-2-independent POA PGE2 increase, (+)-catechin (an antioxidant, 3 µg/µl) was microdialyzed and POA PGE2 and Tc were determined. SIN-1 and carboxy-PTIO reduced and enhanced, respectively, the rises in NE, PGE2 and Tc produced by iv LPS. Similarly, they prevented and increased, respectively, the delayed elevations of PGE2 and Tc induced by intraPOA clonidine. (+)-Catechin prevented the LPS-induced elevation of PGE2, but not of Tc. We conclude that the antipyretic activity of NO derives from its inhibitory modulation of the LPS-induced release of POA NE. These data also implicate free radicals in POA PGE2 production and raise questions about its role as a central LPS fever mediator.
